Researchers from Hainan Medical University, Guangzhou Women and Children’s Medical Center, and other institutions have conducted a study entitled “Adenosine deaminase 2 regulates the activation of the toll-like receptor 9 in response to nucleic acids”. This study was published in Frontiers of Medicine, Volume 18, Issue 5.

Human cells express two types of adenosine deaminases (ADA): ADA1, which is widely present and regulates intracellular functions and extracellular signaling, and ADA2, which is secreted by immune cells. The intracellular functions of ADA2 remain poorly defined compared to ADA1. Toll-like receptor 9 (TLR9) is an intracellular receptor activated by nucleic acids, playing a key role in immune responses against infections and cancer. The aim of this study was to clarify the regulatory role of ADA2 in TLR9 activation. The researchers performed cell isolation and culture, siRNA-mediated ADA2 knockdown, immunostaining, confocal microscopy, and binding assays to investigate the interaction between ADA2 and TLR9 agonists (such as CpG oligodeoxynucleotides) in plasmacytoid dendritic cells (pDCs) and other immune cells.Data analysis revealed that ADA2 is a lysosomal protein that binds to single-stranded DNA (ssDNA), double-stranded DNA (dsDNA), and RNA, with a preference for linear-structured nucleic acids. It specifically interacts with class B and C CpG oligodeoxynucleotides (ODNs) but has low affinity for class A CpG ODNs. ADA2 competes with TLR9 for binding to CpG ODNs in endosomes, thereby inhibiting TLR9 activation. Knockdown of ADA2 expression or blocking ADA2 with specific RNA (such as poly U) significantly enhanced interferon-alpha (IFN-α) secretion from pDCs activated by CpG ODNs or natural DNA. Additionally, IL-3 treatment altered pDC responses to CpG ODNs, which may be related to changes in ADA2 localization or expression. This study not only identifies a novel intracellular function of ADA2 as a regulator of TLR9 activation but also provides potential therapeutic strategies for enhancing immune responses against intracellular infections and cancer.

For more detailed information, the full paper is available at: https://doi.org/10.1007/s11684-024-1067-5.